Various types of bandages for delivering biologically active agents (hereafter referred to generally as "drugs") to the skin at substantially constant rates are known to the art and have been proposed to deliver a wide variety of drugs. As used herein the term "drug" is intended to have its broadest interpretation as any biologically active substance which is administered to a subject to produce a usually beneficial biological effect. U.S. Pat. No. 3,598,122 (which is hereby incorporated by reference) for example, describes a multi-layered bandage comprising a backing layer, a drug reservoir layer, a release-rate controlling membrane and a contact adhesive layer which maintains the bandages in drug delivering contact with the skin. The release-rate controlling element is disposed between the drug and the contact adhesive layer and constitutes a separate element of the device.
U.S. Pat. No. 4,286,592 (which is hereby incorporated by reference) constitutes a significant improvement in this technology by combining into one structural element of the device the function of both the contact adhesive and the rate-controlling membrane. According to this patent, in order to permit the contact adhesive layer to function as both a contact adhesive and a rate-controlling element, a relationship between the diffusion coefficients and solubilities of the drug in the adhesive and the drug reservoir and the thickness of the adhesive must exist. This relationship is defined as follows and which, for convenience will be referred to hereafter as the "Rate Controlling Adhesive Relationship."
(i) the concentration of the drug in the contact adhesive lamina, C.sub.CA (mg/cm.sup.3), is not greater than the solubility of the drug in the contact adhesive composition, C.sub.SCA, and
(ii) the ratio ##EQU1## is in the range of about 0.01 to about 0.7 over a substantial portion of the adminsitration period and wherein:
D.sub.CA is the diffusion coefficient of the drug in the contact adhesive composition in cm.sup.2 /hr,
l.sub.CA is the thickness of the contact adhesive lamina in cm,
D.sub.DR is the diffusion coefficient of the drug in the carrier in cm.sup.2 /hr,
C.sub.DR is the concentration of drug in the drug reservior in mg/cm.sup.3
C.sub.SDR is the solubility of the drug in the carrier in mg/cm.sup.3, and
t, is any time during said administration period in hours, and the term "substantial" as applied to said time period means at least 50%. When the conditions set forth in the Rate-Controlling Relationship are met, the flux of drug from the drug reservoir layer, in the absence of the adhesive layer, will be about 100 times greater than the flux of drug through the adhesive layer when the value of the Relationship is 0.01. When the value of the Relationship is increased to 0.7 the flux of drug from the reservoir layer will have been reduced to a level equal to the flux of drug through the adhesive. This provides a simple laboratory test to determine whether or not the relationship is met without requiring the determination of the values for the individual parameters of the relationship. The in vitro flux of drug can be measured for samples of the reservoir and adhesive compositions and as long as the reservoir flux is from 1 to about 100 times the adhesive flux the relationship will be satisfied.
Of the embodiments disclosed in this patent, the embodiment of Example 1 utilizes similar polyisobutylene/mineral oil (PIB/MO) compositions for both the drug reservoir and adhesive layers. The embodiment of Example 2 utilizes dissimilar materials, silicone oil and an ethylene vinylacetate (EVA) copolymer (9% VA) as the reservoir and adhesive, respectively. The embodiment of Example 1, possesses better characteristics in terms of structural integrity and adhesive properties but, as disclosed in the patent, the diffusion coefficient and solubility of the agent through the drug reservoir and the adhesive layers of Example 1 are substantially the same. The release characteristics of the device of Example I could be improved if the matrix or carrier composition of the drug reservoir possessed a substantially higher permeability than the contact adhesive composition, as in Example 2, but by so doing some compromises in structural integrity and adhesive properties are made.
One of the desirable characteristics of PIB/MO adhesives (as used herein, "mineral oil" includes both natural and synthetic mineral oils), is their high permeability to many drugs. For this reason, prior to our invention, we were unaware of any transdermal delivery device which conformed to the Rate Controlling Adhesive Relationship which utilized a drug reservoir matrix composition other than a PIB/MO composition in combination with a PIB/MO adhesive. According to our invention we have provided a combination of dissimilar reservior and adhesive compositions which enable the devices of our invention to use a PIB/MO adhesive and also posses improved the long-term release characteristics.
It is accordingly an object of this invention to provide improved transdermal delivery devices employing release-rate controlling adhesives.
It is another object of this invention to provide a combination of a drug reservoir matrix material with a PIB/MO adhesive material which permit a drug delivery device to conform to the Rate Controlling Adhesive Relationship.
It is another object of this invention to provide a transdermal delivery device for administering timolol.
It is another object of this invention to provide a transdermal delivery device for administering atropine.
These and other objects of the invention will be readily apparent from the following description with reference to the accompanying drawings wherein: